The goal of this Program Project has been and continues to be the multi-disciplinary study of the etiology of gastric cancer. This neoplastic disease is second only to lung cancer in incidence and mortality worldwide. In the United States gastric cancer rates have decreased considerably. There are, however, high-risk groups, especially African Americans, Amerindians, and immigrants from Asia, Northern/Eastern Europe and Latin America. It has become increasingly clear that a major etiologic factor is chronic infection with Helicobacter pylori. About one half of today.s world population is infected, especially groups of lower socioeconomic status. The International Agency for research on Cancer has classified Helicobacter infection as a class 1 carcinogen. There are great differences in the outcome of the infection. Most infections are mild and subclinical. Clinical infections may lead to duodenal ulcer accompanied by non-atrophic gastritis, which does not increase gastric cancer risk, or to multifocal atrophic gastritis, which may lead to gastric ulcer and gastric cancer. Our general hypothesis is that the immune and inflammatory responses determine the outcome of the infection. Our Program Project explores the dynamics of the response with immunologic and histopathologic techniques in adults and children (Project 1,2 and 3). Two epidemiologic projects are also proposed: 1) follow-up of the chemoprevention cohort, which explores the natural history of infection after eradication attempts (Project 1); and 2) study of the dynamics of infection and reinfection in children of a hyper-endemic area in search for answers to the critical events in initiating the possible carcinogenesis pathway, namely persistence of infection in childhood. (Project 3). COLLABORATING INSTITUTION(S): Delft laboratories, The Netherlands Emory University Medical Center Atlanta, GA University del Valle, Cali, Colombia University de Narino, Colombia University de Antioquia, Medellin, Colombia University of Texas School of Public Health, Houston TX APR NOTE: This Program Project Grant has addressed the etiology of gastric cancer for 20 years and is in the fifth cycle of funding. This competitive renewal application continues the unique and multidisciplinary study of gastric cancer. The general hypothesis put forward by this Program Project is that the immune and inflammatory responses determine the outcome of the Helicobacter pylori infection leading to gastric ulcer or gastric cancer. The Program includes 3 Projects and 4 Cores. It was felt at the accelerated review that the investigators had resolved all the problems identified in the last review. The Program Project has continued to build on the broad clinical, pathological, and molecular experience accumulated by the Principal Investigator and his program project staff. Two unique populations of H. pylori-infected individuals located in Colombia are being studied. In one population non-atrophic gastritis (NAG) is more common along with low gastric cancer rates and in the second population multi-focal atrophic gastritis (MAG) is more common with a much higher gastric cancer rate. A major strength of this research and the Program Project is the investigators' matchless understanding of the etiology of gastric cancer in these unique and well-characterized populations. These two populations (a major world-wide resource for studying H. pylori pathogenesis) constitute the major strength of this application along with the more than 18 years of study of this gastric cancer problem by the Principal Investigator in a program project environment. In a previous review there were problems with some of the work not being adequately described for an accurate assessment of its feasibility, but these deficiencies have been eliminated. The program is totally unique, has been highly successful in the past, and should make substantial progress in this new funding period. The recommended merit scores of all three projects was 1.4. Three of the cores, Histopathology, Administrative and Field Activites, and Genetic Characterization are rated superior, and the Administrative and Data Management Core is rated satisfactory. The Program is highly integrated and in a very special way makes the whole more valuable than the parts. This was a unanimous observation by the reviewers. The Program is recommended for 5 years of funding. Project 1, """"""""Chemoprevention of gastric Dysplasia"""""""", is led by Elizabeth Fontham, Ph.D. The focus of this project continues to be an important population from Colombia who are at high risk for gastric cancer and who have been the focus of this program project since its inception. A unique cohort of subjects with MAG from this population were the subjects of an interventional study in the 1990's to examine the effect of beta carotene and Vitamin C and/or eradication of H. pylori on the progression of gastric precancerous histological lesions. Contact has been maintained with these subjects, around half of who are now H. pylori-negative. This project will continue to follow these subjects closely by endoscopy and clinical evaluation to determine whether the continuing natural history of progression in gastric preneoplasia is altered by the persistent eradication of H. pylori. A secondary aim will be to determine whether those subjects who become reinfected by H. pylori are infected by less virulent strains, as suggested by preliminary data. The project has many strengths, including its focus on a unique and well-defined clinically relevant population, and the expertise of the clinicians and pathologists, who have proven their ability to work cohesively under the supervision of Drs Correa and Fontham over many years. This project received an average merit rating of 1.4. Project 2. """"""""Immune Response to H. pylori in Non-atrophic Gastritis and Multifocal Gastritis"""""""" is led by Augusto Ochoa, M.D. It has continued to improve since the first review. One major exception was the validation of using PBL responses to reflect the immune and inflammatory status of leukocytes in the gastric mucosa. This was addressed satisfactorily in the accelerated peer review. The investigators responded by stating that for the first third of the patients analyzed (numbering 20), in vitro PBL responses will be compared with in situ gastric tissue responses. If concordance is observed, the remaining patients in the study will be followed as initially proposed, with concentration of efforts on PBL analysis. If, on the other hand, concordance between the PBL vs. in situ tissue analysis is not observed, the investigators will be able to adjust their analysis to include both PBL's and in situ analysis of all remaining subjects. This response is entirely appropriate and alleviates the biggest uncertainty in the approach taken in Project 2 during the previous submission. The greatest strengths of this project include the unique patient resources available and the previous productivity of the investigators. The overall goal of defining differences in the host immune response between H. pylori-infected patients at risk of developing gastric cancer versus duodenal ulcers is very worthwhile, and within the capability of the investigators. The project has the potential to help dissect the relative contributions of host and bacteria to the development of gastric cancer. This project received an average merit rating of 1.4. Project 3, """"""""Community Intervention-Follow-up of Colombian Children"""""""" is led by Karen Goodman in a consortium arrangement with The University of Texas School of Public Health. This project addresses important questions in an appropriate fashion. In the previous version of this project, a clerical effort resulting in the reviewers not seeing the final draft. This problem has been resolved with many of the perceived scientific problems also being clarified. The 3-drug therapy chosen was identified by the reviewers as """"""""a peculiar combination"""""""". In the most recent submission, Metronidazole has been added to create a 4-drug therapy. This regimen is consistent with contemporary medical practices. This project received a merit rating of 1.4 Core A, Histopathology, is led by the Principal Investigator, Dr. Pelayo Correa. This laboratory will perform all the histological and histochemical processing and evaluation of the numerous biopsies taken from each of the projects. It is a critically important core for this program project. It will be essential for all three projects, especially Project 1. This laboratory has proven over many years that it is ideally equipped for these purposes, and Dr Correa, the Core director, has an unequalled expertise in the interpretation of gastric pathology. This is a superior core. Core B, """"""""Genetic Characterization of H. pylori Strains"""""""" led by Barbara Schneider, Ph.D., provides resources for genotypic characterization of three putative virulence genes in H. pylori strains. . The LiPA assay for this purpose is well validated and supported by the experience of its inventor, Dr. van Doorn, who will serve as a consultant. The high-throughput advantages of the LiPA assay will be exploited in Projects 1 and 2. It is not clear whether babA typing will also be done by LiPA or by other, independent PCR's. In addition development of non-invasive genotyping methods using fecal samples is proposed. This core received a superior rating. Core C, """"""""Administrative and Data Management (New Orleans)"""""""" is led by Dr. Pelayo Correa, M.D. who is also the Principal Investigator of this grant application. This administrative effort has been quite successful in the past and is very well organized and efficient. This Core had the deficiency during the last review of an underpowered statistical analysis effort. Dr. Correa has addressed this deficiency, and both Ms. Du and Ms. Camargo have been assigned to work under Dr. Mera. The question during the last review was regarding the amount of time Dr. Mera could devote to this Program Project. His credentials are perfectly matched for this Program Project, but his time available was considered inadequate because of the large amount of statistical analysis needed by this Program Project. To satisfy this criticism, two new faculty were recruited the biostatistics area. One of these individuals, Dr. Velasco, is Spanish speaking and could help the program project and reports to Dr. Fontham, the Project Leader of Project 1. Most importantly, the new head of the Cancer Center Statistical Department (just hired the week of the current review at the full professor level) will give 15 percent of his time to this Program. This individual is highly qualified and very experienced with the types of statistical problems that will occur in these studies. Thus, the program project statistical effort is going to be run 25 percent time by Dr. Mera and 15% by the new senior faculty member with 2 capable support people at LSU. This is a strong addition to the Core and resolves the major statistical problem from the last review. This core received a satisfactory rating. Core D, """"""""Administrative and Field Activities (Colombia)"""""""" is led by Luis Eduardo Bravo, M.D. As was stated previously this is an outstanding core. The cost effectiveness of this effort is remarkable. Past history of this effort and the intact staff from the previous funding period make this core effort convincing and very workable. Some of the details missing about data flow and quality assurance from the previous review were not entirely provided in this new submission, but the effort is still superior, as the overall coordination between the various units in Colombia and between Colombia and the US look strong. This core received a superior rating. Commentary related to Progress in the current funding period, Integrated Effort, Principal Investigator, Support to be negotiated for replacement and Human Subjects are unchanged from the previous review. REVISION NOTE: Modified to include review panel roster. INDIVIDUAL PROJECTS AND CORES PROJECT 1: Chemoprevention of Gastric Dysplasia: Long-term follow-up of a cohort treatment for H. pylori infection (Elizabeth T.H. Fontham, Dr. Ph.H., 15 percent effort)
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